The orphan cytokine, macrophage migration inhibitory factor (MIF), is a pleiotropic, pro-inflammatory mediator, released by numerous cell types including endothelial cells, eosinophils, macrophages, lymphocytes and neutrophils. MIF exerts numerous biological effects and plays a key role in the inflammatory and autoimmune processes through the induction of TNF-α, IL-1, IL-8, cyclooxygenase and nitric oxide release by macrophages. Furthermore, MIF is involved in the down regulation of the oncogenic protein p53 and can counter act the production of glucocorticoids. Consequently, MIF has been implicated in the pathogenesis of a number of inflammatory disease states including sepsis, atherosclerosis, lupus, rheumatoid arthritis, asthma, glomerulonephritis and acute respiratory distress syndrome (ARDS). Its role in cancer biology has also recently been highlighted. Unusually for a cytokine, MIF contains a well-defined enzymatic site, which acts as a keto-enol tautomerase. It is believed that this tautomerase site plays a role in the numerous biological effects displayed by MIF.
MIF exists as a symmetrical trimer consisting of 3 repeating, 12.5 KDa, 114 residue subunits each with β-α-β homology. Unusually, aside from its role as a cytokine, MIF also displays two distinct catalytic activities: a keto-enol tautomerase and a thiol mediated oxidoreductase. The MIF trimer consists of three hydrophobic keto-enol tautomerase active sites which each span two subunits. The N-terminal proline residue of each subunit resides within the active site and displays a low pKa of around 5.6-6. The nucleophilic character of this residue enables it to catalyze the isomerization of a number of substrates including 4-hydroxy phenyl pyruvate (HPP), phenyl pyruvic acid and D-Dopachrome.
MIF is overexpressed in numerous cancers including lung cancer, ovarian cancer, breast cancer, hepatocellular cancer, oesophageal squamous-cell cancer, bladder cancer, cervical squamous-cell cancer, pancreatic cancer, glioblastomas, prostate cancer, osteosarcoma, colorectal cancer, head and neck cancer and malignant melanoma, gastric cancer, glioma, nasopharyngeal cancer.
As a key player in several cancers, clearly the development of novel inhibitors of MIF, which could potentially serve as chemotherapeutics in the treatment of the aforementioned disease states is highly desirably.
In WO2012142498, Gaweco describes quinolinone compounds which demonstrate MIF inhibitory activity.
Similarly, in US2007270395 Jagadish describes quinolinone compounds and quinoline compounds which demonstrate MIF inhibitory activity. Said compounds are said to have utility in the treatment of inflammatory bowel disease.